Novel Intermediate Used for Preparing Tapentadol or Analogues Thereof

ABSTRACT

The invention discloses a novel intermediate for preparing tapentadol and analogues thereof, wherein the structural formula is shown as formula I or II, and the groups are defined as the specification. The invention further discloses a method for preparing the novel intermediate and use of the intermediate for preparing tapentadol and analogues thereof. The invention can remarkably improve the product yield and quality of tapentadol, reduce the production cost, and simplify the production procedure. The preparation process is environment friendly, thus more suitable for the requirements of industrial production.

CROSS REFERENCE TO RELATED PATENT APPLICATION

This application is a division application of U.S. application Ser. No.13/884,810 filed on May 10, 2013, which claims the priority right ofPCT/CN 2011/001248 filed on Jul. 29, 2011.

FIELD OF THE INVENTION

The invention belongs to the field of pharmaceutical preparation, andrelates to a novel intermediate for preparing tapentadol and analoguesthereof.

BACKGROUND OF THE INVENTION

Tapentadol hydrochloride is the hydrochloride of tapentadol, and a novelcentral analgesic with dual mechanism of action developed by Johnson &Johnson Inc. in USA. It is used as medicine in the form of single isomerof (1R,2R), molecular formula: C₁₄H₂₄ClNO, chemical name:(1R2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride.The structural formula is as follows:

Tapentadol belongs to the 1-phenyl-3-(dimethylamine) propane compoundwhich has various pharmacological activities, and can be used forrelieving pain (EP963475), also for treating psychosis (DE102007012165),depression (DE10233048), urinary incontinence (WO2002043715), etc.

Tapentadol hydrochloride was on the market under the approval of U.S.Food and Drug Administration on Nov. 21, 2008, and the clinic showedthat it has good analgesic effect. Tapentadol hydrochloride is not onlya μ opiate receptor agonist, but a norepinephrine reuptake inhibitor(Tzschentke T M, et al., J. Pharm. Exper. Therap., 2007, 323, 265), withthe analgesic effect on various animal subjects suffering from acute,inflammatory and chronic neuropathic pains. Its effect is betweenmorphine and tramadol, and the satisfied plasma drug concentration canbe reached by intravenous injection or oral administration. It has goodtolerance, and is difficult to produce analgesic tolerance and physicaldependence compared with morphine. The side effect (especially thegastrointestinal side effect) is further improved compared with thestrong opioids of the equivalent analgesic dosage, so the prospect inthe treatment of acute and chronic moderate to severe pains is betterand better.

The chemical structures of tapentadol and analogues thereof have beendisclosed in EP-A-0,693,475 where the prepared precursor of tapentadol,(2R,3R)-3-(3-methoxy-phenyl)-N,N,2-trimethylamylamine, is obtained bycontinuously converting(2R,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentanol intothe relevant halide by thionyl chloride, removing the tertiary hydroxylon (2R,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentanol,and removing chlorine by zinc borohydride, zinc cyanoborohydride and/ortin cyanoborohydride. The defect of this process is that the halide isobtained by the excessive strong chloridizing agent, thionyl chloride.And, from the point of view of fire and health, it is too hazardous byusing the hydriding reagent, such as zinc borohydride, zinccyanoborohydride and tin cyanoborohydride, in the industrial scale.

Tapentadol is obtained by converting(2S,3S)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentanol intothe mixture of (2R,3R) and(2R,3S)-3-(3-methoxy-phenyl)-N,N,2-trimethylpentylamine by the preparedprecursors in WO-2004/108658 and WO-2005/00078. The two replacementmethods are characterized in that the obtained3-(3-methoxy-phenyl)-N,N,2-trimethylpentylamine is the mixture of(2R,3R) and (2R,3S) stereoisomers and must be separated to obtain therequired (2R,3R) stereoisomer.

Based on EP-A-0,693,475, the improvement has been made inCN200780028472.6 where(2R,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methyl-3-pentanol issubject to hydrogenolysis by a palladium catalyst. This reaction iscarried out under the condition of high temperature catalysis, so thereaction condition is very rigour and the requirement on reactionequipment is higher, resulting in inconvenience for the actualproduction.

SUMMARY OF THE INVENTION

To overcome the shortcomings of the current methods for preparingtapentadol above, the invention provides a novel method for preparingtapentadol and analogues thereof, and a novel intermediate compound forpreparing tapentadol and analogues thereof and a preparation method ofthe intermediate. Tapentadol or salts and analogues thereof can beobtained by preparation through the novel intermediate easily. Theimplementation of the invention can remarkably improve the product yieldof tapentadol (total yield: 12.3%) and product quality (chemicalpurity>99.5% (HPLC), optical ee %>99%), greatly reduce the productioncost, and simplify the production procedure (the multi-step product canbe used for the next reaction directly without refinement). Thepreparation process is environment friendly (all the reagents used forthe reactions comply with the requirements of Guideline for ResidualSolvents: ICH), thus more suitable for the requirements of industrialproduction (reaction condition mild and no special equipment required).

The first objective of the invention is to provide a novel intermediatecompound for preparing tapentadol and analogues thereof.

A compound shown as formula I or II has the following structuralformula:

where

R₁ is selected from halogen, hydroxy, amino, nitrile, nitro, acyl,substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxyl, substituted orunsubstituted aryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl,acyloxy, oxyacyl and sulfonyl;

X is selected from oxygen or sulfur;

Y is selected from halogen, OR₂ or NR₃R₄;

R₂ is selected from substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, substitutedor unsubstituted aralkyl, substituted or unsubstituted heteroaryl, andsubstituted or unsubstituted heteroaralkyl; and

R₃ and R₄ are separately selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heteroaralkyl; or R₃, R₄ and N form saturated orunsaturated heterocyclyl jointly.

The substituted in the invention refers to that the position capable ofbeing substituted on the group may be substituted by any suitable normalgroups, with no special limit.

The alkyl in the invention is preferably selected from straight orbranched alkyl containing 1 to 6 carbon atoms.

The alkoxyl in the invention is preferably selected from straight orbranched alkoxyl containing 1 to 6 carbon atoms.

The cycloalkyl in the invention is preferably selected from monocyclicsaturated carbon ring group containing 3 to 7 carbon atoms.

The aryl in the invention is preferably selected from unsaturated carbonring group containing 5 to 12 carbon atoms.

The heteroaryl in the invention is preferably selected from unsaturatedcyclic group containing 5 to 12 carbon atoms and 1 to 3 oxygen, nitrogenor sulfur atoms.

The aralkyl and heteroaralkyl in the invention are preferably selectedfrom the combinations of the groups above.

The acyl in the invention refers to the group containing —C(═O).

The acyloxy in the invention refers to the group containing —C(═O)O.

The oxyacyl in the invention refers to the group containing —OC(═O).

The sulfonyl in the invention refers to the group containing —(═O)S(═O).

R₁ is selected from F, Cl, Br, CHF₂, CF₃, OH, SO₂CH₃, NH₂, CN, CHO,—C₁₋₆ alkyl, —C₁₋₆ alkoxyl, —C₃₋₇ cycloalkyl, —C₁₋₃ alkylenephenyl,—C₁₋₃ alkylenenaphthyl, tetrahydrofuran or —C(═O) C₁₋₆ alkyl.

R₁ is further preferably selected from Cl, methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, n-pentyl, methoxy, propoxyl, ethoxyl,isopropoxyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, OH, or NH₂. R₁ is most preferably selected from Cl, methyl,OH, NH₂ or methoxy.

When Y is selected from OR₂, R₂ is preferably selected from thesaturated alkyl containing 1 to 3 atoms and further preferably selectedfrom methyl, ethyl, propyl or isopropyl.

When Y is selected from NR₃R₄, preferably, R₃ and R₄ are separatelyselected from hydrogen, substituted or unsubstituted saturated alkyl; orR₃, R₄ and N form substituted or unsubstituted saturatednitrogen-containing heteorcyclyl containing oxygen or not jointly.

When Y is selected from NR₃R₄, furthermore, R₃ and R₄ are preferably andseparately selected from hydrogen, methyl, ethyl, propyl or isopropyl;or R₃, R₄ and N form tetrahydropyrrole ring, piperidine ring,4-methylpiperidine ring, morpholine ring, methylpiperazine ring or4-hydroxypiperidine jointly; and R₃ and R₄ are preferably selected frommethyl, ethyl, propyl or isopropyl at the same time.

The compounds in the invention are preferably selected from thefollowing compounds:

Number Name Structural Formula  1 valeryl 2-methyl-3- (3-methoxyphenyl)chloride

 2 methyl 2-methyl-3- (3-methoxyphenyl) valerate

 3 methyl 2-methyl-3- (3-methoxyphenyl) sulfovalerate

 4 methyl 2-methyl-3- (3-hydroxyphenyl) valerate

 5 methyl 2-methyl-3- (3-hydroxyphenyl) valerate

 6 2-methyl-3- (3-hydroxyphenyl) sulfovaleramide

 7 N,N-dimethyl-2- methyl-3-(3- methoxyphenyl) valeramide

 8 N,N-dimethyl-2- methyl-3-(3- methoxyphenyl) sulfoveramide

 9 N,N-dimethyl-2- methyl-3-(3- hydroxyphenyl) valeramide

10 N,N-dimethyl-2- methyl-3-(3- hydroxyphenyl) sulfovaleramide

11 N,N-diethyl-2- methyl-3-(3- methoxyphenyl) valeramide

12 N,N-dipropyl-2- methyl-3-(3- methoxyphenyl) valeramide

13 N,N-isopropyl-2- methyl-3-(3- methoxyphenyl) valeramide

14 3-(3- methoxyphenyl)- 2-methyl-1- (piperidin-1-yl) pentan-1-one

15 3-(3- methoxyphenyl)- 2-methyl-1-(4- methylpiperidin- 1-yl)pentan-1-one

16 3-(3- methoxyphenyl)- 2-methyl-1- (morpholin-1-yl) pentan-1-one

17 3-(3- methoxyphenyl)- 2-methyl-1- (pyrrolidin-1-yl) pentan-1-one

18 N,N-dimethyl-2- methyl-3-(3- chlorophenyl) valeramide

19 N,N-diethyl-2- methyl-3-(3- chlorophenyl) valeramide

20 N,N-dipropyl-2- methyl-3-(3- chlorophenyl) valeramide

21 N,N-isopropyl-2- methyl-3-(3- chlorophenyl) valeramide

22 3-(3-chlorophenyl)- 2-methyl-1- (piperidin-1-yl) pentan-1-one

23 3-(3-chlorophenyl)- 2-methyl-1-(4- methylpiperidin- 1-yl)pentan-1-one

24 3-(3-chlorophenyl)- 2-methyl-1- (morpholin-1-yl) pentan-1-one

25 3-(3-chlorophenyl)- 2-methyl-1- (pyrrolidin-1-yl) pentan-1-one

26 N,N-dimethyl- 2-methyl-3-(3- methylphenyl) valeramide

27 N,N-diethyl-2- methyl-3-(3- methylphenyl) valeramide

28 N,N-dipropyl- 2-methyl-3-(3- methylphenyl) valeramide

29 N,N-isopropyl-2- methyl-3-(3- methylphenyl) valeramide

30 3-(3-methylphenyl)- 2-methyl-1- (piperidin-1-yl) pentan-1-one

31 3-(3-methylphenyl)- 2-methyl-1-(4- methylpiperidin- 1-yl)pentan-1-one

32 3-(3-methylphenyl)- 2-methyl-1- (morpholin-1-yl) pentan-1-one

33 3-(3-methylphenyl)- 2-methyl-1- (pyrrolidin-1-yl) pentan-1-one

34 N,N-dimethyl- 2-methyl-3-(3- aminophenyl) valeramide

35 N,N-diethyl-2- methyl-3-(3- aminophenyl) valeramide

36 N,N-dipropyl- 2-methyl-3-(3- aminophenyl) valeramide

37 N,N-isopropyl- 2-methyl-3-(3- aminophenyl) valeramide

38 3-(3-aminophenyl)- 2-methyl-1- (piperidin-1-yl) pentan-1-one

39 3-(3-aminophenyl)- 2-methyl-1-(4- methylpiperidin- 1-yl)pentan- 1-one

40 3-(3-aminophenyl)- 2-methyl-1- (morpholin-1-yl) pentan-1-one

41 3-(3-aminophenyl)- 2-methyl-1- (pyrrolidin-1-yl) pentan-1-one

42 2-methyl-3- (3-hydroxyphenyl) pentanenitrile

43 2-methyl-3- (3-methoxyphenyl) pentanenitrile

The compounds in the invention as the intermediate are used forpreparing tapentadol and analogues thereof. The compounds in theinvention preferably form tapentadol and analogues thereof after thesalt is obtained by asymmetric preparation or chiral separation.

The methods for preparing the compound of formula I in the invention areexplained hereinafter, and are not intended to limit the composition ofthe invention.

The compound of formula I in the invention can be prepared by thefollowing methods, however, the conditions of the methods below, such asreactor, solvent, acid, alkali, reaction temperature and time, are notlimited to the explanations below. The compounds in the invention can beconveniently prepared by combining various preparation methods in thespecification or known in the field, so those skilled in the art of theinvention can easily implement such combinations.

The compounds above are prepared by the following methods in theinvention.

Method 1 is shown as Scheme 1:

where the substitution reaction is to react bromide with substitutedmalonates in a solvent, and is carried out under the condition suitablefor catalyzing alkaline compounds;

the hydrolysis decarboxylation reaction is to hydrolyze the relevantsubstituted malonate into substituted malonic acid in an alkalineaqeuous solution to obtain the target compound by high temperaturedecarboxylation; and

the acylation reaction is to react with an acylating reagent, such asthionyl chloride, phosphorus pentachloride and phosphorus tribromide toobtain an acyl halide compound, i.e., compound I.

Method 2 is shown as Scheme 2:

where the reduction reaction is to reduce carbonyl into hydroxyl by areducer which may be hydrogen, metal oxide, such as sodium borohydrideand lithium aluminum hydride;

the halogenation reaction is to substitute hydroxyl with the relevanthalogen, and the halogenating reagent may be thionyl chloride,phosphorus pentachloride, phosphorus tribromide or the like; and

the substitution reaction is to react a cyanide with the halogenationreaction product to obtain the relevant target compound II, and thecyanide may be sodium cyanide, cuprous cyanide or the like.

In the reaction route above, R₁, R₂, X and Y are defined as above; X₁and X₂ are selected from oxygen or sulfur, and they may be same or not;R₅ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted aralkyl, substituted or unsubstitutedheteroaryl, and substituted or unsubstituted heteroaralkyl.

The method for the preparing tapentadol by using the compound in theinvention as the intermediate is as follows:

where the amidation reaction is to react compound I with the relevantamide to obtain the relevant amide compound;

the reduction reaction is to reduce the amide into the relevant aminecompound by using a proper reducer which usually is hydrogen, borane,sodium borohydride, lithium aluminum hydrid or the like;

the hydrolysis reaction is to hydrolyze the relevant cyanide in anaqueous solution with a certain pH to obtain the relevant amidecompound;

the alkylation reaction is to alkylate N on the primary amine by arelevant alkylating reagent which may be haloalkane, such aschloromethane, chloroethane, bromomethane, bromoethane and iodomethane,an ester compound, such as dimethyl sulfate, diethyl sulfate, trimethylphosphate and methyl p-toluenesulfonate, aldehyde or ketone of variousaliphatics or aromatics, or the like; and

the separation step is to separate the prepared racemic compound into asingle chiral compound by a relevant chiral separator which is an acidicchiral separator, and through the HPLC detection, the content of thechiral compound is 99.56%, and ee %>99.5%.

In the reaction route above, R₁, R₂, R₃, R₄, X and Y are defined asabove; and preferably, R₁ is hydroxyl, R₂, R₃ and R₄ are methyl, and theproduct is tapentadol.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The embodiments below explain the invention more specifically. However,it should be construed that such embodiments are only for explaining theinvention by examples, instead of limiting the scope of the invention inany forms.

Embodiment 1 Preparation of diethyl 2-(3-methoxphenyl)propylmalonate

The steps are: add diethyl methylmalonate and anhydrous DMF into areaction flask, stir well, T=40, add NaH, after 1-hour consecutivereaction dip the DMF solution of 3-(1-bromopropyl)anisole whilestirring, stir at 85 for 18 hours, track that the reaction issubstantially completed by TLC (developer: petroleum ether/ethyl acetate(8:1)), pour the reaction product in the water, perform extraction byethyl acetate until the water layer is not fluorescent, wash the organiclayer twice by water without drying to obtain a yellow oily productafter decompression and concentration, i.e., diethyl2-(3-methoxphenyl)propylmalonate.

Molecular formula: C₁₈H₂₆O₅, molecular weight: 322.4, MS(m/z): 322.

Elementary analysis: theoretical values: C, 67.06%; H, 8.13%; measuredvalues: C, 67.16%; H, 8.19%.

Embodiment 2 Preparation of 2-methyl-3-(3-methoxyphenyl)valeric acid

The steps are: add diethyl 2-(3-methoxphenyl)propylmalonate, ethanol andwater into a reaction flask, adjust the pH value to 14 by sodiumhydroxide after stirring them well, perform heating reflux reaction,track the reaction by TLC, keep the pH value of the solution at 14,(developer: petroleum ether/ethyl acetate (4:1)), distil ethanol bydecompression, and perform extraction twice by ethyl acetate to separatean organic layer out; adjust the pH value of the water layer to 2 to 3by an acid, perform extraction by ethyl acetate, separate organic layersout, combine the organic layers, and perform drying by anhydrousmagnesium sulphate to obtain a yellow oily product after decompressionand concentration; add the yellow oily production in a three-neck flask,reflux and heat it in an oil bath of 15 for 5 hours, pour the resultantinto the sodium hydroxide solution to make the pH become alkaline, andexact the undissolved substance by ethyl acetate; and adjust the pH ofthe water layer to 3 by hydrochloric acid, perform extraction by ethylacetate, and distil a solvent out after drying and decompression toobtain a yellow liquid, i.e., 2-methyl-3-(3-methoxyphenyl)valeric acid.

Molecular formula: C₁₃H₁₈O₃, molecular weight: 222.3, MS(m/z): 223(M⁺+H).

Elementary analysis: theoretical values: C, 70.24%; H, 8.16%; measuredvalues: C, 70.32%; H, 8.09%.

¹H-NMR (CDCl₃, 500 MHz):

δ: 7.09 (t, J=8.5 Hz, 1H, Ar—H), 6.77 (d, J=8.5 Hz, 2H, Ar—H), 6.77 (d,J=8.5 Hz, 1H, Ar—H), 3.90 (s, 3H, —OCH₃), 3.10 (m, 1H, Ar—CH), 2.90 (m,1H, Ar—CH—CH—COOH), 1.62 (m, 2H), 1.19 (d, J=6.5 Hz, 3H), 0.73 (d, J=6.0Hz, 3H); ¹³C-NMR (CDCl₃, 125 MHz) δ: 176.0, 160.1, 139.6, 127.3, 123.1,116.3, 113.1, 60.3, 56.8, 55.8, 44.5, 26.5, 14.3, 11.2.

Embodiment 3 Preparation of 2-methyl-3-(3-hydroxyphenyl)valeric acid

The steps are: add 2-methyl-3-(3-methoxyphenyl)valeric acid into areaction flask, add hydroiodic acid, and perform heating and reflux for12 hours; detect the reaction process by TLC; after that, cool theresultant to the room temperature, pour it into an alkaline solution tomake the pH become 9, perform extraction by ethyl acetate, reverselyadjust the pH of the water layer to about 3.0 after the water layer isseparated out, and add ethyl acetate for extraction; and dry the ethylacetate extracting solution by anhydrous magnesium sulphate, and recyclethe solvent by decompression to obtain a light yellow liquid,2-methyl-3-(3-hydroxyphenyl)valeric acid.

Molecular formula: C₁₈H₂₆O₅, molecular weight: 208.3, MS(m/z): 209(M⁺+H).

Elementary analysis: theoretical values: C, 69.21%; H, 7.74%; measuredvalues: C, 65.35%; H, 7.56%.

Embodiment 4 Preparation of valeryl 2-methyl-3-(3-methoxyphenyl)chloride(compound 1)

The steps are: add 2-methyl-3-(3-hydroxyphenyl)valeric acid into athree-neck flask, add thionyl chloride, perform reflux for 4 hours,detect that the reaction is substantially completed by TLC, (developer:petroleum ether/ethyl acetate (4:1)); and distil a solvent bydecompression to obtain valeryl 2-methyl-3-(3-methoxyphenyl)chloride(compound 1).

Molecular formula: C₁₃H₁₇ClO₂, molecular weight: 240.7, MS(m/z): 240(M⁺).

Elementary analysis: theoretical values: C, 64.86%; H, 7.12%; measuredvalues: C, 65.02%; H, 7.24%.

Embodiment 5 Preparation of methyl 2-methyl-3-(3-methoxyphenyl)valerate(compound 2)

The steps are: add compound 1 and methanol into a three-neck flask,perform reflux for 5 hours, detect that the reaction is substantiallycompleted by TLC, distil a solvent by decompression to obtain a lightyellow oily product, valeryl 2-methyl-3-(3-methoxyphenyl)chloride(compound 2).

Molecular formula: C₁₄H₂₀O₃, molecular weight: 236.3, MS(m/z): 236 (M⁺).

Elementary analysis: theoretical values: C, 71.16%; H, 8.53%; measuredvalues: C, 71.09%; H, 8.39%.

Embodiment 6 Preparation ofN,N-dimethyl-2-methyl-3-(3-methoxyphenyl)valeramide (compound 7)

The step are: add the aqueous solution of dimethylamine (33%) into athree-neck flask, T=10, dip compound 1 and NaOH to make pH=12 to 14;after that, keep performing the reaction at the room temperature for 2hours; perform extraction twice by ethyl acetate, prepare the organicphase, rinse twice by 10% hydrochloric acid, and perform drying byanhydrous magnesium sulfate; recycle the solvent by decompression toobtain a light yellow oily product which is dissolved by isopropanol;and add a seed crystal to obtain a white solid,N,N-dimethyl-2-methyl-3-(3-methoxyphenyl)valeramide (compound 7).

Molecular formula: C₁₅H₂₃NO₂, molecular weight: 249.4, MS(m/z): 249(M⁺).

Elementary analysis: theoretical values: C, 72.25%; H, 9.30%; N, 5.62%;measured values: C, 72.31%; H, 9.35%; N, 5.73%.

Embodiment 7 Preparation ofN,N-dimethyl-2-methyl-3-(3-hydroxyphenyl)valeramide (compound 9)

The steps are: add compound 7 into a reaction flask, add hydroiodicacid, perform heating and reflux for 5 hours; detect the reactionprocess by TLC; after that, cool the resultant to the room temperature,pour it to an alkaline solution to make the pH become 9, and performextraction by ethyl acetate and rinse by water; and recycle the solventafter drying and decompression to obtain a light yellow liquid,N,N-dimethyl-2-methyl-3-(3-hydroxyphenyl)valeramide (compound 9).

Molecular formula: C₁₄H₂₁NO₂, molecular weight: 235.3, MS(m/z): 235(M⁺).

Elementary analysis: theoretical values: C, 71.46%; H, 8.99%; N, 5.95%;measured values: C, 71.33%; H, 9.05%; N, 5.92%.

¹H-NMR (CDCl₃, 500 MHz) δ: 7.11 (t, J=8.0 Hz, 1H, Ar—H), 6.74 (d, J=8.0Hz, 2H, Ar—H), 6.62 (d, J=8.0 Hz, 1H, Ar—H), 3.03 (m, 2H, Ar—CH,Ar—CH—CH—COOH), 2.86 (s, 6H, N(CH₃)₂), 1.66 (m, 2H), 1.12 (d, J=6.5 Hz,3H), 0.75 (d, J=6.0 Hz, 3H); ¹³C-NMR (CDCl₃, 125 MHz) δ: 176.0, 158.3,140.6, 129.3, 121.8, 114.9, 113.6, 59.2, 42.7, 39.4, 26.5, 15.2, 11.1.

Embodiment 8 Preparation ofN,N-diethyl-2-methyl-3-(3-methoxyphenyl)valeramide (compound 11)

Compound 11 can be obtained by replacing dimethylamine in Embodiment 6with diethylamine.

Molecular formula: C₁₇H₂₇NO₂, molecular weight: 277.4, MS(m/z): 277(M⁺).

Elementary analysis: theoretical values: C, 73.61%; H, 9.81%; N, 5.05%;measured values: C, 73.43%; H, 9.75%; N, 5.09%.

Embodiment 9 Preparation ofN,N-dipropyl-2-methyl-3-(3-methoxyphenyl)valeramide (compound 12)

Compound 12 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 6 with dipropylamine.

Molecular formula: C₁₉H₃₁NO₂, molecular weight: 305.5, MS(m/z): 305(M⁺).

Elementary analysis: theoretical values: C, 74.71%; H, 10.23%; N, 4.59%;measured values: C, 74.68%; H, 10.21%; N, 4.61%.

Embodiment 10 Preparation ofN,N-diisopropyl-2-methyl-3-(3-methoxyphenyl)valeramide (compound 13)

Compound 13 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 6 with diisopropylamine.

Molecular formula: C₁₉H₃₁NO₂, molecular weight: 305.5, MS(m/z): 305(M⁺).

Elementary analysis: theoretical values: C, 74.71%; H, 10.23%; N, 4.59%;measured values: C, 74.74%; H, 10.30%; N, 4.56%.

Embodiment 11 Preparation of3-(3-methoxyphenyl)-2-methyl-1-(piperidin-1-yl)pentan-1-one (compound14)

Compound 14 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 6 with piperidine.

Molecular formula: C₁₈H₂₇NO₂, molecular weight: 289.4, MS(m/z): 289(M⁺).

Elementary analysis: theoretical values: C, 74.70%; H, 9.40%; N, 4.84%;measured values: C, 74.79%; H, 9.35%; N, 4.77%.

Embodiment 12 Preparation of3-(3-methoxyphenyl)-2-methyl-1-(4-methylpiperidin-1-yl)pentan-1-one(compound 15)

Compound 15 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 6 with 4-methylpiperidine.

Molecular formula: C₁₉H₂₉NO₂, molecular weight: 303.45, MS(m/z): 304(M⁺+1).

Elementary analysis: theoretical values: C, 75.21%; H, 9.63%; N, 4.62%;measured values: C, 75.19%; H, 9.57%; N, 4.76%.

Embodiment 13 Preparation of3-(3-methoxyphenyl)-2-methyl-1-(morpholin-1-yl)pentan-1-one (compound16)

Compound 16 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 6 with morpholine.

Molecular formula: C₁₇H₂₅NO3, molecular weight: 291.39, MS(m/z): 291(M⁺).

Elementary analysis: theoretical values: C, 70.07%; H, 8.65%; N, 4.81%;measured values: C, 70.11%; H, 8.57%; N, 4.79%.

Embodiment 14 Preparation of3-(3-methoxyphenyl)-2-methyl-1-(pyrrolidin-1-yl)pentan-1-one (compound17)

Compound 17 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 6 with pyrrolidine.

Molecular formula: C₁₇H₂₅NO₂, molecular weight: 275.39, MS(m/z): 275(M⁺).

Elementary analysis: theoretical values: C, 74.14%; H, 9.15%; N, 5.09%;measured values: C, 74.12%; H, 9.17%; N, 4.98%.

Embodiment 15 Preparation ofN,N-dimethyl-2-methyl-3-(3-chlorophenyl)valeramide (compound 18)

Compound 18 can be obtained according to the operation of the method byreplacing 3-(1-bromopropyl)anisole in Embodiment 1 with3-(1-bromopropyl)chlorobenzene.

Molecular formula: C₁₄H₂₀ClNO, molecular weight: 253.77, MS(m/z): 253(M⁺).

Elementary analysis: theoretical values: C, 66.26%; H, 7.94%; N, 5.52%;measured values: C, 66.32%; H, 8.05%; N, 5.56%.

Embodiment 16 Preparation of N,N-diethyl-3-(3-chlorophenyl)-2-methylvaleramide (compound 19)

Compound 19 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 12 with diethylamine.

Molecular formula: C₁₆H₂₄ClNO, molecular weight: 281.83, MS(m/z): 281(M⁺).

Elementary analysis: theoretical values: C, 68.19%; H, 8.58%; N, 4.97%;measured values: C, 68.22%; H, 8.65%; N, 4.86%.

Embodiment 17 Preparation of 3-(3-chlorophenyl)-2-methyl-N,N-dipropylvaleramide (compound 20)

Compound 20 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 12 with dipropylamine.

Molecular formula: C₁₈H₂₈ClNO, molecular weight: 309.88, MS(m/z): 309(M⁺).

Elementary analysis: theoretical values: C, 69.77%; H, 9.11%; N, 4.52%;measured values: C, 69.83%; H, 9.21%; N, 4.56%.

Embodiment 18 Preparation of 3-(3-chlorophenyl)-2-methyl-N,N-isopropylvaleramide (compound 21)

Compound 21 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 12 with isopropylamine.

Molecular formula: C₁₇H₂₄ClNO, molecular weight: 293.84, MS(m/z): 294(M⁺).

Elementary analysis: theoretical values: C, 69.77%; H, 9.11%; N, 4.52%;measured values: C, 69.84%; H, 9.23%; N, 4.59%.

Embodiment 19 Preparation of3-(3-chlorophenyl)-2-methyl-1-(piperidin-1-yl)pentan-1-one (compound 22)

Compound 22 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 12 with piperidine.

Molecular formula: C₁₇H₂₄ClNO, molecular weight: 293.84, MS(m/z): 294(M⁺).

Elementary analysis: theoretical values: C, 69.49%; H, 8.23%; N, 12.07%;measured values: C, 69.44%; H, 8.31%; N, 4.75%.

Embodiment 20 Preparation of3-(3-chlorophenyl)-2-methyl-1-(4-methylpiperidin-1-yl)pentan-1-one(compound 23)

Compound 23 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 12 with 4-methylpiperidine.

Molecular formula: C₁₈H₂₆ClNO, molecular weight: 307.87, MS(m/z): 307(M⁺).

Elementary analysis: theoretical values: C, 70.23%; H, 8.51%; N, 4.55%;measured values: C, 70.22%; H, 8.65%; N, 4.62%.

Embodiment 21 Preparation of3-(3-chlorophenyl)-2-methyl-1-(morpholin-1-yl)pentan-1-one (compound 24)

Compound 24 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 12 with morpholine.

Molecular formula: C₁₈H₂₆ClNO, molecular weight: 307.87, MS(m/z): 307(M⁺).

Elementary analysis: theoretical values: C, 64.97%; H, 7.50%; N, 4.73%;measured values: C, 65.02%; H, 7.55%; N, 4.68%.

Embodiment 22 Preparation of3-(3-chlorophenyl)-2-methyl-1-(pyrrolidin-1-yl)pentan-1-one (compound25)

Compound 25 can be obtained according to the operation of the method byreplacing dimethylamine in Embodiment 12 with pyrrolidine.

Molecular formula: C₁₆H₂₂ClNO, molecular weight: 279.81, MS(m/z): 279(M⁺).

Elementary analysis: theoretical values: C, 68.68%; H, 7.93%; N, 5.01%;measured values: C, 68.70%; H, 7.02%; N, 5.12%.

Embodiment 23 Preparation of 3-(3-methoxy-phenyl)-N,N,2-trimethylpentylamine

The steps are: add anhydrous ether into a reaction flask, and addlithium aluminum hydride under the condition of ice bath; dip compound7, control the temperature within 10, after the dipping detect thereaction process by TLC; after the reaction is ended, pour the reactionliquid in the ice water slowly, separate the ether layer out, rinse bywater, perform drying, and recycle the solvent by decompression toobtain a light yellow liquid, 3-(3-methoxy-phenyl)-N,N,2-trimethylpentylamine. Yield: 85%.

Molecular formula: C₁₅H₂₅NO, molecular weight: 235.4, MS(m/z): 235 (M⁺).Embodiment 24 Preparation of 3-(3-hydroxy-phenyl)-N,N,2-trimethylpentylamine

The steps are: add 3-(3-methoxy-phenyl)-N,N,2-trimethyl pentylamine intoa reaction flask, add hydroiodic acid, and perform heating and refluxfor 5 hours; detect the reaction process by TLC; after that, cool theresultant to the room temperature, pour it to an alkaline solution tomake the pH become 9, perform extraction by ethyl acetate and rinse bywater; recycle the solvent by drying and decompression to obtain a lightyellow liquid, 3-(3-hydroxy-phenyl)-N,N,2-trimethyl pentylamine; andseparate the mother solution by a separator, form the salt by theacidification of hydrochloric acid to obtain tapentadol hydrochloride.HPLC, 99.56%, ee %>99.5%.

Molecular formula: C₁₄H₂₃NO.HCl, molecular weight: 257.8, MS(m/z): 221(M⁺-HCl).

Elementary analysis: theoretical values: C, 65.23%; H, 9.38%; N, 5.43%;measured values: C, 65.31%; H, 9.35%; N, 5.31%.

¹H-NMR (D₂O, 500 MHz) δ: 7.15 (t, J=8.0 Hz, 1H, Ar—H), 6.69 (dd, J=8.0Hz, 2H, Ar—H), 6.65 (d, J=8.0 Hz, 1H, Ar—H), 2.71 (m, 2H, —CH₂), 2.62(s, 6H, N(CH₃)₂), 2.20 (m, 1H, —CH—CH₃), 2.04 (m, 1H, —CH—), 1.73, 1.42(m, 2H, —CH₂CH₃), 0.96 (d, 3H, —CHCH₃), 0.54 (t, 3H, —CH₂CH₃).

Embodiment 25 Preparation of 3-(3-methoxy-phenyl)-2-methyl-N,N-diethylpentylamine

3-(3-methoxy-phenyl)-2-methyl-N,N-diethyl pentylamine can be obtained bycompound 11 according to Embodiment 23.

Molecular formula: C₁₇H₂₉NO, molecular weight: 263.4, MS(m/z): 264(M⁺+H).

Elementary analysis: theoretical values: C, 77.51%; H, 11.09%; N, 5.31%;measured values: C, 77.39%; H, 11.15%; N, 5.42%.

Embodiment 26 Preparation of(1R,2R)-3-(3-diethylamine-1-ethyl-2-methylpropyl)-phenol hydrochloride

(1R,2R)-3-(3-diethylamine-1-ethyl-2-methylpropyl)-phenol hydrochloridecan be obtained by 3-(3-methoxy-phenyl)-2-methyl-N,N-diethyl pentylamineaccording to Embodiment 24.

Molecular formula: C₁₆H₂₇NO.HCl, molecular weight: 285.8, MS(m/z): 249(M⁺-HCl).

Elementary analysis: theoretical values: C, 71.21%; H, 10.46%; N, 5.19%;measured values: C, 71.11%; H, 10.35%; N, 5.21%.

Embodiment 27 Preparation of 3-(3-methoxy-phenyl)-2-methyl-N,N-dipropylpentylamine

3-(3-methoxy-phenyl)-2-methyl-N,N-dipropyl pentylamine can be obtainedby compound 12 according to Embodiment 23.

Molecular formula: C₁₉H₃₃NO, molecular weight: 291.5, MS(m/z): 290(M⁺−H).

Elementary analysis: theoretical values: C, 78.29%; H, 11.41%; N, 4.81%;measured values: C, 78.33%; H, 11.52%; N, 4.76%.

Embodiment 28 Preparation of(1R,2R)-3-(3-dipropylamine-1-ethyl-2-methylpropyl)-phenol hydrochloride

(1R,2R)-3-(3-dipropylamine-1-ethyl-2-methylpropyl)-phenol hydrochloridecan be obtained by 3-(3-methoxy-phenyl)-2-methyl-N,N-dipropylpentylamine according to Embodiment 24.

Molecular formula: C₁₈H₃₁NO.HCl, molecular weight: 313.9, MS(m/z): 277(M⁺-HCl).

Elementary analysis: theoretical values: C, 68.87%; H, 10.28%; N, 4.46%;measured values: C, 68.74%; H, 10.33%; N, 4.36%.

Embodiment 29 Preparation of3-(3-methoxy-phenyl)-2-methyl-N,N-diisopropyl pentylamine

3-(3-methoxy-phenyl)-2-methyl-N,N-isopropyl pentylamine can be obtainedby compound 13 according to Embodiment 23.

Molecular formula: C₁₉H₃₃NO, molecular weight: 291.5, MS(m/z): 290(M⁺−H).

Elementary analysis: theoretical values: C, 78.29%; H, 11.41%; N, 4.81%;measured values: C, 78.33%; H, 11.52%; N, 4.76%.

Embodiment 30 Preparation of(1R,2R)-3-(3-diisopropylamine-1-ethyl-2-methylpropyl)-phenolhydrochloride

(1R,2R)-3-(3-isopropylamine-1-ethyl-2-methylpropyl)-phenol hydrochloridecan be obtained by 3-(3-methoxy-phenyl)-2-methyl-N,N-dipropylpentylamine according to Embodiment 24.

Molecular formula: C₁₈H₃₁NO.HCl, molecular weight: 313.9, MS(m/z): 277(M⁺-HCl).

Elementary analysis: theoretical values: C, 68.87%; H, 10.28%; N, 4.46%;measured values: C, 68.74%; H, 10.33%; N, 4.36%.

Embodiment 31 Preparation of1-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-piperidine

1-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-piperidine can be obtained bycompound 14 according to Embodiment 23.

Molecular formula: C₁₈H₂₉NO, molecular weight: 275.4, MS(m/z): 275 (M⁺).

Elementary analysis: theoretical values: C, 78.49%; H, 10.61%; N, 5.09%;measured values: C, 78.42%; H, 10.55%; N, 5.21%.

Embodiment 32 Preparation of(1R,2R)-3-(1-ethyl-2-methyl-3-piperidin-1-yl-propyl)-phenolhydrochloride

(1R,2R)-3-(1-ethyl-2-methyl-3-piperidin-1-yl-propyl)-phenolhydrochloride can be obtained by1-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-piperidine according toEmbodiment 24.

Molecular formula: C₁₇H₂₇NO.HCl, molecular weight: 297.9, MS(m/z): 261(M⁺-HCl).

Elementary analysis: theoretical values: C, 72.44%; H, 10.01%; N, 4.97%;measured values: C, 72.36%; H, 10.15%; N, 5.02%.

Embodiment 33 Preparation of1-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-4-methyl-piperidine

1-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-4-methyl-piperidine can beobtained by compound 15 according to Embodiment 23.

Molecular formula: C₁₉H₃₃NO, molecular weight: 291.5, MS(m/z): 291 (M⁺).

Elementary analysis: theoretical values: C, 78.29%; H, 11.41%; N, 4.80%;measured values: C, 78.31%; H, 11.35%; N, 4.82%.

Embodiment 34 Preparation of(1R,2R)-3-[1-ethyl-2-methyl-3-(4-methyl-piperidin-1-yl)-propyl]-phenolhydrochloride

(1R,2R)-3-[1-ethyl-2-methyl-3-(4-methyl-piperidin-1-yl)-propyl]-phenolhydrochloride can be obtained by1-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-4-methyl-piperidine accordingto Embodiment 24.

Molecular formula: C₁₈H₂₉NO.HCl, molecular weight: 311.89, MS(m/z): 275(M⁺-HCl).

Elementary analysis: theoretical values: C, 69.31%; H, 9.70%; N, 4.49%;measured values: C, 69.42%; H, 9.72%; N, 4.46%.

Embodiment 35 Preparation of4-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-morpholine

4-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-morpholine can be obtained bycompound 16 according to Embodiment 23.

Molecular formula: C₁₇H₂₇NO₂, molecular weight: 277.4, MS(m/z): 277(M⁺).

Elementary analysis: theoretical values: C, 73.60%; H, 9.81%; N, 5.05%;measured values: C, 73.71%; H, 9.85%; N, 5.01%.

Embodiment 36 Preparation of(1R,2R)-3-(1-ethyl-2-methyl-4-morpholin-4-yl-propyl)-phenolhydrochloride

(1R,2R)-3-(1-ethyl-2-methyl-3-morpholin-4-yl-propyl)-phenolhydrochloride can be obtained by4-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-morpholine according toEmbodiment 24.

Molecular formula: C₁₆H₂₇NO₂.HCl, molecular weight: 299.8, MS(m/z): 263(M⁺-HCl).

Elementary analysis: theoretical values: C, 64.09%; H, 8.74%; N, 4.67%;measured values: C, 64.12%; H, 9.79%; N, 4.71%.

Embodiment 35 Preparation of1-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-pyrrolidine

1-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-pyrrolidine can be obtainedby compound 17 according to Embodiment 23.

Molecular formula: C₁₇H₂₇NO, molecular weight: 261.4, MS(m/z): 261 (M⁺).

Elementary analysis: theoretical values: C, 78.11%; H, 10.41%; N, 5.35%;measured values: C, 78.24%; H, 10.35%; N, 5.29%.

Embodiment 36 Preparation of(1R,2R)-3-(1-ethyl-2-methyl-3-pyrrolidin-4-yl-propyl)-phenolhydrochloride

(1R,2R)-3-(1-ethyl-2-methyl-3-pyrrolidin-1-yl-propyl)-phenolhydrochloride can be obtained by1-[3-(3-methoxyphenyl)-2-methyl-pentalkyl]-pyrrolidine according toEmbodiment 24.

Molecular formula: C₁₄H₂₃NO.HCl, molecular weight: 283.8, MS(m/z): 247(M⁺-HCl).

Elementary analysis: theoretical values: C, 67.70%; H, 9.23%; N, 5.64%;measured values: C, 67.76%; H, 9.31%; N, 5.59%.

Embodiment 37 Preparation of 3-(3-methoxyphenyl)-2-pentanol

The steps are: under the condition of ice bath, add methanol and3-(3-methoxyphenyl)-2-pentanol into a reaction flask, stir, introduceN₂, after the system is reduced about 0 add 96% sodium borohydride forfour times, keep performing the reaction at the temperature for 30minutes, track that the reaction is substantially completed by TLC,distil the solvent by decompression, pour the reaction product in thewater, and perform extraction by ethyl acetate and drying by anhydrousmagnesium sulfate to obtain 3-(3-methoxyphenyl)-2-pentanol afterdecompression and concentration, yield: 99%.

Molecular formula: C₁₂H₁₈O2, molecular weight: 194.3, MS(m/z): 195(M⁺+H).

Elementary analysis: theoretical values: C, 74.19%; H, 9.34%; measuredvalues: C, 74.22%; H, 9.32%.

Embodiment 38 Preparation of 1-(2-bromopentane)-3-methoxybenzene

The steps are: under the protection of N₂, add3-(3-methoxyphenyl)-2-pentanol and dichloromethane into a reactionflask, lower the temperature to about −5 by ice bath, dip PBr₃, keep thetemperature, stir at the temperature for 1 hour, track that the reactionis substantially completed by TLC, pour the reaction product in the icewater, perform extraction by dichloromethane, rinse the organic layer bythe aqueous solution of sodium bicarbonate and then by water, andperform drying by anhydrous magnesium sulfate to obtain1-(2-bromopentane)-3-methoxybenzene after decompression andconcentration, yield: 95%.

Molecular formula: C₁₂H₁₇BrO, molecular weight: 256.2, MS(m/z): 257(M⁺+H).

Elementary analysis: theoretical values: C, 56.04%; H, 6.66%; measuredvalues: C, 56.11%; H, 6.62%.

Embodiment 39 Preparation of 2-methyl-3-(3-methoxyphenyl)pentanenitrile(compound 43)

The steps are: add sodium cyanide and DMF into a reaction flask, risethe temperature to 85, dip the DMF solution of1-(2-bromopentane)-3-methoxybenzene, keep the temperature, stir at thetemperature for 8 hours, track that the reaction is substantiallycompleted by TLC, and lower the temperature to the room temperature; andpour the reaction liquid in the water, perform extraction by ethylacetate until the water layer is not fluorescent, and rinse the organiclayer twice by water without drying to obtain2-methyl-3-(3-methoxyphenyl)pentanenitrile after decompression andconcentration.

Molecular formula: C₁₃H₁₇NO, molecular weight: 203.3, MS(m/z): 204(M⁺+H).

Elementary analysis: theoretical values: C, 76.81%; H, 8.43%; measuredvalues: C, 76.75%; H, 8.46%.

The invention has been described in connection with the embodiments. Itshould be construed that the description and embodiments above are onlyused for explaining the invention by examples. Various replacements andimprovements of the invention can be made by those skilled in the artwithin the spirit and scope of the invention and should be construed tobe within the protection scope of the invention

1. A compound shown as formula I, comprising the following structuralformulas:

wherein R₁ is selected from halogen, hydroxy, amino, nitrile, nitro,acyl, substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkoxyl, substituted orunsubstituted aryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl,acyloxy, oxyacyl and sulfonyl; X is selected from oxygen or sulfur; Y isselected from halogen, OR₂ or NR₃R₄; R₂ is selected from substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heteroaralkyl; and when X is selected from sulphur, R₃ andR₄ are separately selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaryl, and substituted or unsubstitutedheteroaralkyl; or R₃, R₄ and N form saturated or unsaturatedheterocyclyl jointly; when X is selected from oxygen, R₃ and R₄ areseparately selected from substituted or unsubstituted cycloalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheteroaralkyl; or R₃, R₄ and N for saturated or unsaturated heterocycly.2. The compound according to claim 1, wherein R₁ is selected from Cl,methyl, OH hydroxy, NH₂ amino or methoxy.
 3. The compound according toclaim 1, characterized in that Y is selected from OR₂, wherein R₂ isselected from methyl, ethyl, n-propyl or isopropyl.
 4. The compoundaccording to claim 1, characterized in that Y is selected from NR₃R₄,wherein R₃, R₄ and N form substituted or unsubstituted saturatednitrogen-containing heteorcyclyl containing oxygen or not jointly. 5.The compound according to claim 4, wherein R₃, R₄ and N formtetrahydropyrrole ring, piperidine ring, 4-methylpiperidine ring,morpholine ring, methylpiperazine ring or 4-hydroxypiperidine jointly.6. The compound according to claim 1, selected from the followingcompounds: valeryl 2-methyl-3-(3-methoxyphenyl)chloride; methyl2-methyl-3-(3-methoxyphenyl)sulfovalerate; methyl2-methyl-3-(3-hydroxyphenyl)sulfovalerate;2-methyl-3-(3-hydroxyphenyl)sulfovaleramide;N,N-dimethyl-2-methyl-3-(3-methoxyphenyl)sulfovaleramide;N,N-dimethyl-2-methyl-3-(3-hydroxyphenyl)sulfovaleramide;N,N-diethyl-2-methyl-3-(3-methoxyphenyl)valeramide;3-(3-methoxyphenyl)-2-methyl-1-(piperidin-1-yl)pentan-1-one;3-(3-methoxyphenyl)-2-methyl-1-(4-methylpiperidin-1-yl)pentan-1-one;3-(3-methoxyphenyl)-2-methyl-1-(morpholin-1-yl)pentan-1-one;3-(3-methoxyphenyl)-2-methyl-1-(pyrrolidin-1-yl)pentan-1-one;3-(3-chlorophenyl)-2-methyl-1-(piperidin-1-yl)pentan-1-one;3-(3-chlorophenyl)-2-methyl-1-(4-methylpiperidin-1-yl)pentan-1-one;3-(3-chlorophenyl)-2-methyl-1-(morpholin-1-yl)pentan-1-one;3-(3-chlorophenyl)-2-methyl-1-(pyrrolidin-1-yl)pentan-1-one;3-(3-methylphenyl)-2-methyl-1-(piperidin-1-yl)pentan-1-one;3-(3-methylphenyl)-2-methyl-1-(4-methylpiperidin-1-yl)pentan-1-one;3-(3-methylphenyl)-2-methyl-1-(morpholin-1-yl)pentan-1-one;3-(3-methylphenyl)-2-methyl-1-(pyrrolidin-1-yl)pentan-1-one;3-(3-aminophenyl)-2-methyl-1-(piperidin-1-yl)pentan-1-one;3-(3-aminophenyl)-2-methyl-1-(4-methylpiperidin-1-yl)pentan-1-one;3-(3-aminophenyl)-2-methyl-1-(morpholin-1-yl)pentan-1-one;3-(3-aminophenyl)-2-methyl-1-(pyrrolidin-1-yl)pentan-1-one.
 7. Thecompound according to claim 1, wherein the compound is used as anintermediate for preparing tapentadol and analogues thereof.
 8. Thecompound according to claim 7, wherein the reaction route for preparingtapentadol and analogues thereof is:

where R₁, R₂, R₃, R₄, X and Y are defined as claim 1; and preferably R₁is hydroxyl, and R₂, R₃ and R₄ are methyl.